JP2000063356A - Production of fluoroheterocyclic compound and fluoroheterocyclic compound thus produced - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain the subject compound useful as an intermediate for synthesizing physiologically active fluoro (iso) quinoline derivatives by reacting a specific difluorostyrene derivative with a specific nucleophile or base. SOLUTION: This fluoroheterocyclic compound of formula II [Y is CR2=N, N=CH or (R3SOn)N-CH2] is obtained by reaction between a β,β-difluorostyrene derivative of formula I [R1 is a 1-8C alkyl; X is isocyano or R3SOnNHCH2 group (R3 is phenyl optionally substituted with 1-3C alkyl (s), a 1-3C alkyl or the like; (n) is 1 or 2)] and a nucleophile of the formula (R2) (R2 is a 1-8C alkyl) or base of the formula MH (M is an alkali metal). For example, one of the objective compounds, 4-butyl-3-fluoro-2-tosyldihydroisoquinoline, is obtained by reacting sodium hydride with 2-o-(N-tosylaminomethyl)phenyl-1,1-difluoro-1- hexene.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a fluorine-containing heterocyclic compound.

[0002]

2. Description of the Related Art Certain halogen-containing quinoline derivatives are useful as an active ingredient of pesticide herbicides (for example, quinclorac), and some 3
-Fluoroisoquinoline derivatives are known to have antimalarial activity (gametogenic activity against malaria parasite) (J. Med. Chem., 1970, vol. 37, 613-616). Under such circumstances, the physiological activity of the fluorinated quinoline derivative and the fluorinated isoquinoline derivative has been attracting attention in the field of medicine and agricultural chemicals, and the fluorinated quinoline derivative and the fluorinated isoquinoline derivative useful as intermediates for the production of the fluorinated quinoline derivative and the fluorinated isoquinoline derivative have been attracting attention. Development of an efficient production method of a fluorine heterocyclic compound is desired.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a fluorine-containing quinoline derivative from a β, β-difluorostyrene derivative,
An object of the present invention is to provide an efficient method for producing a fluorine-containing isoquinoline derivative and a fluorine-containing dihydroisoquinoline derivative. Another object is to provide a fluorine-containing quinoline derivative, a fluorine-containing isoquinoline derivative and a fluorine-containing dihydroisoquinoline derivative.

[0004]

Means for Solving the Problems As a result of intensive studies by the present inventors, a β, β-difluorostyrene derivative represented by the following general formula 6 and a nucleophilic species represented by the following general formula 7 or the following general formula The present inventors have found that a fluorine-containing heterocyclic compound represented by the following general formula (9) can be efficiently produced by reacting with a base represented by the following chemical formula (8), and completed the present invention. That is, the present invention has the general formula

[Chemical 6] [In the formula, R ¹ represents a C1-C8 alkyl group (for example, an n-butyl group, a sec-butyl group, etc.), and X represents an isocyano group or an R ³ SO _n NHCH ₂ group. {Where R ³ is C 1
To a phenyl group which may be substituted with a C3 alkyl group (for example, a trifluoromethyl group), a C1 to C3 alkyl group or a C1 to C3 fluoroalkyl group, and n is 1
Or represents 2. }]], A β, β-difluorostyrene derivative represented by the general formula:

Embedded image (R ² ) ^— [In the formula, R ² represents a C1-C8 alkyl group (for example, n-butyl group, tert-butyl group, iso-butyl group, etc.). ] Or a general formula

[Image Omitted] MH (wherein M represents an alkali metal (for example, sodium atom or potassium atom)) is reacted with a base represented by the general formula:

[Chemical 9] [Group wherein, -Y- is represented by -CR ² = N-, -N =
Group or the formula represented by _{^{CH- - (R 3 SO n)}} N-CH 2
Represents a group represented by-, and R ¹ , R ² , R ³ and n have the same meanings as described above. ] The manufacturing method of the fluorine-containing heterocyclic compound shown by these (henceforth a manufacturing method of this invention) is provided. The present invention is further represented by the general formula

[Chemical 10] [In the formula, R ⁴ represents a C2-C5 alkyl group, -Z- represents a group represented by -CR ⁵ = N-, a group represented by formula -N = CH- or a formula-(R ³ SO _n ) NH. It represents a group represented by —CH ₂ —. Here, R ⁵ represents a C2-C5 alkyl group,
R ³ and n have the same meanings as described above. ] The fluorine-containing heterocyclic compound shown by these is provided.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The manufacturing method of the present invention will be described in detail below.

(Production method of the present invention-1) A method of reacting a β, β-difluorostyrene derivative represented by the general formula 6 in which X is an isocyano group with a nucleophilic species represented by the general formula 7. The reaction is usually performed in an inert solvent under an atmosphere of an inert gas (eg, nitrogen gas, argon gas, etc.). The reaction temperature range is −80 ° C. to 100 ° C., and the reaction time range is 0.1 hour to 30 hours. Examples of the solvent include halogenated hydrocarbons such as dichloromethane, hydrocarbons such as toluene, hexane and cyclohexane, ethers such as diethyl ether and tetrahydrofuran, hexamethylphosphoric triamide (hereinafter, referred to as H
It is referred to as MPA. ) Or a mixed solvent thereof. The amount of the nucleophilic species represented by the general formula (7) is the β, β-difluorostyrene derivative 1 represented by the general formula (6).
The amount is usually 1.0 to 1.5 mol with respect to mol. The reaction solution after completion of the reaction is treated with water or a buffer solution if necessary, and then subjected to post-treatment operations such as extraction with an organic solvent and concentration to give the desired quinoline derivative represented by the following general formula (14). Obtainable. The compound can be further purified, if necessary, by operations such as chromatography and distillation.

Examples of the β, β-difluorostyrene derivative represented by the general formula 6 in which X is an isocyano group include 2-o-isocyanophenyl-1,1-difluoro-1.
-Hexene 2-o-isocyanophenyl-1,1-difluoro-3
General formula 11 such as -methyl-1-pentene

[Chemical 11] [In the formula, R ¹ represents the same meaning as described above. ] Β,
Examples include β-difluorostyrene derivatives. In the production method of the present invention, the nucleophilic species represented by the general formula:
For example, general formula 12

Embedded image in R ²¹ Li [wherein, R ²¹ represents a C1~C8 alkyl group. ] Or an organic lithium compound represented by the general formula:

Embedded image in R ²¹ MGZ [wherein, Z is a chlorine atom, a bromine atom or an iodine atom, R ²¹ are as defined above. ] Organ-magnesium compound represented by the above formula. Examples of such an organolithium compound include tert-butyllithium and the like, and examples of the organomagnesium compound include n-butylmagnesium bromide and iso-propylmagnesium chloride. Examples of the fluorine-containing hetero compound produced by the production method 1 of the present invention include 2,4-dibutyl-3-fluoroquinoline 2-butyl-4-sec-butyl-3-fluoroquinoline 2-iso-propyl-4-. Butyl-3-fluoroquinoline 2-tert-butyl-4-butyl-3-fluoroquinoline, etc.

[Chemical 14] [In the formula, R ¹ and R ² have the same meanings as described above. ] The quinoline derivative shown by these is mentioned.

(Production method of the present invention-2) X is R ³ SO _n NHC
A method of reacting a β, β-difluorostyrene derivative represented by the general formula (6), which is an H ₂ group, with a base represented by the general formula (8). The reaction is usually performed in an inert solvent under an atmosphere of an inert gas (eg, nitrogen gas, argon gas, etc.). The reaction temperature range is −80 ° C. to 100 ° C., and the reaction time range is 0.5 hour to 30 hours. Examples of the solvent include halogenated hydrocarbons such as dichloromethane, hydrocarbons such as toluene, hexane and cyclohexane, ethers such as diethyl ether and tetrahydrofuran, N, N-dimethylformamide (hereinafter, D
It is written as MF. ) Or a mixed solvent thereof.
The amount of the base represented by the general formula:
The ratio is usually 1.1 to 3.0 mol relative to 1 mol of the β, β-difluorostyrene derivative represented by. The reaction solution after completion of the reaction is treated with water or a buffer solution if necessary, and then subjected to post-treatment operations such as extraction with an organic solvent and concentration to obtain the desired isoquinoline derivative represented by the following general formula 16 The dihydroisoquinoline derivative represented by the general formula 17 can be obtained. The compound is
It can be further purified by operations such as chromatography and distillation. The production ratio of the isoquinoline derivative and the dihydroisoquinoline derivative produced can be changed depending on the type of base used, the type of solvent used, the reaction temperature and the like.

A general formula in which X is an R ³ SO _n NHCH ₂ group
Examples of the β, β-difluorostyrene derivative represented by Chemical formula 6 include 2-o- (N-tosylaminomethyl) phenyl-1,1
-Difluoro-1-hexene 2-o- (N-tosylaminomethyl) phenyl-1,1
-Difluoro-3-methyl-1-pentene etc.

[Chemical 15] [In the formula, R ¹ and R ³ represent the same meaning as described above. ] The β, β-difluorostyrene derivative represented by Examples of the base represented by the general formula 8 include sodium hydride and potassium hydride.
Examples of the fluorine-containing hetero compound produced by the production method-2 of the present invention include 4-butyl-3-fluoroisoquinoline 4-sec-butyl-3-fluoroisoquinoline 4-butyl-3-fluoro-2-tosyldihydroisoquinoline 4 General formula of -sec-butyl-3-fluoro-2-tosyldihydroisoquinoline and the like

[Chemical 16] [In the formula, R ¹ represents the same meaning as described above. ] The isoquinoline derivative represented by

[Chemical 17] [In the formula, R ¹ and R ³ represent the same meaning as described above. ] The dihydroisoquinoline derivative shown by these is mentioned.

The β, β-difluorostyrene derivative represented by the general formula 6 is, for example, Tetrahedron Letters, 19
92,33,3779-3782, Tetrahedron Letters, 1996,37,8799
-8802 etc. can be manufactured according to the method.
Alternatively, it can also be synthesized by the method shown in Scheme 18 below.

[Chemical 18] [In the formula, Ts represents a tosyl group, ⁿ Bu group represents an ⁿ -butyl group, ^s Bu group represents a sec-butyl group, and Boc
Represents a tert-butoxycarbonyl group, DEAD represents diethyl azodicarboxylate, THF represents tetrahydrofuran, cat. Represents a catalytic amount, Pd ₂
(Dba) ₃ represents tris (dibenzylideneacetonyl) bispalladium, rt represents room temperature, HMPA represents hexamethylphosphoric triamide, and Ac represents an acetyl group. ]

[0011]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1: 4-Butyl-3-fluoro-2
-Preparation of tosyldihydroisoquinoline To a solution of 9 mg of sodium hydride (dispersion of mineral oil having a content of 60.0%, 0.22 mmol) in 0.5 ml of DMF at 0 ° C under a nitrogen atmosphere, 2-o- (N-tosylamino). Methyl) phenyl-1,1-difluoro-1-hexene 75 mg (0.20 mmol) DMF 1.5 m
1 solution was added. The reaction solution was stirred at room temperature for 4.5 hours, and then a phosphate buffer solution (pH 7) was added. The aqueous layer was extracted with diethyl ether (three times), the extracted organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure. It was subjected to silica gel column chromatography (developing solvent: pentane: diethyl ether = 5: 1, containing triethylamine 1%) to obtain 63 mg of 4-butyl-3-fluoro-2-tosyldihydroisoquinoline. Yield 89%. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 0.91 (3H, t, J = 7.5 H
z), 1.29-1.43 (4H, m), 2.23 (3H, s), 2.45 (2H, td,
J = 7.5 Hz, J _HF = 2.5 Hz), 4.79 (2H, d, J _HF = 3.7 H
z), 6.88 (1H, dd, J = 7.3, 1.5 Hz), 6.91-6.95 (1H,
m), 6.92 (2H, dd, J = 7.9, 0.6 Hz), 7.00-7.07 (2
H, m), 7.42-7.46 (2H, m). ¹⁹ F-NMR (471 MHz, CDCl ₃ / C ₆ F ₆ ) 65.0 (1F, t, J _FH = 3
Hz) ppm.

Example 2: Preparation of 4-butyl-3-fluoroisoquinoline To a solution of 85 mg of potassium hydride (content of 33.0% mineral oil dispersion, 0.70 mmol) in 1 ml of DMF,
2-o- (N-tosylaminomethyl) phenyl-1,1-difluoro-1-hexene 1 at 0 ° C. under nitrogen atmosphere
A solution of 04 mg (0.27 mmol) in DMF (2 ml) was added. The reaction solution was stirred at room temperature for 4 hours, and then a phosphate buffer solution (pH 7) was added. The aqueous layer was extracted with ethyl acetate (3
After that, the extracted organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure. The residue was subjected to silica gel thin layer chromatography (developing solvent: hexane). : Ethyl acetate = 3: 1) to obtain 53 mg of 4-butyl-3-fluoroisoquinoline. Yield 9
5%. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 0.97 (3H, t, J = 7.5 H
z), 1.46 (3H, tq, J = 7.5, J _HF = 0.9 Hz), 1.63-1.71
(2H, m), 3.03 (2H, tq, J = 7.5 Hz, J _HF = 0.9 Hz),
7.52 (1H, ddd, J = 7.9, 7.9 Hz, J _HF = 0.8 Hz), 7.7
1 (1H, dd, J = 7.6, 7.6 Hz), 7.97 (1H, d, J = 8.2 H
z), 7.99 (1H, d, J = 8.9 Hz), 8.80 (1H, s). ¹⁹ F-NMR (471 MHz, CDCl ₃ / C ₆ F ₆ ) 79.3 (1F, s) ppm.

Example 3: Preparation of 4-sec-butyl-3-fluoro-2-tosyldihydroisoquinoline To a solution of sodium hydride (10 mg, 60.0% mineral oil dispersion, 0.24 mmol) in DMF (1 ml) was added nitrogen. 2-o- (N-tosylaminomethyl) phenyl-1,1-difluoro-3-methyl-1-pentene 82 mg (0.22 mmol) in DM under atmosphere at 0 ° C.
F1.5 ml solution was added. The reaction solution was stirred at room temperature for 9 hours, and then a phosphate buffer solution (pH 7) was added. The aqueous layer was extracted with diethyl ether (three times), the extracted organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure. It was subjected to column chromatography (developing solvent: pentane: diethyl ether = 10: 1, containing 1% of triethylamine) to obtain 69 mg of 4-sec-butyl-3-fluoro-2-tosyldihydroisoquinoline. Yield 89%. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 0.84 (3H, t, J = 7.3 H
z), 1.23 (3H, dd, J = Hz, J _HF = 1.1 Hz), 1.56-1.74
(2H, m), 2.22 (3H, s), 2.61 (1H, td, J = 7.3, 7.3 H
z), 4.74 (1H, dd, J = 16.5, J _HF = 3.6 Hz), 4.80 (1
H, dd, J = 16.5, J _HF = 3.6 Hz), 6.90 (2H, d, J = 8.
2 Hz), 6.93-6.98 (2H, m), 6.99-7.05 (2H, m), 7.40
(2H, d, J = 8.2Hz). ¹⁹ F-NMR (471 MHz, CDCl ₃ / C ₆ F ₆ ) 69.3 (1F, s) ppm.

Example 4: Preparation of 4-sec-butyl-3-fluoroisoquinoline To a solution of 70 mg potassium hydride (33.0% mineral oil dispersion, 0.57 mmol) in 1 ml DMF at 0 ° C. under nitrogen atmosphere. , 2-o- (N-tosylaminomethyl) phenyl-1,1-difluoro-3-methyl-1-
Pentene 83 mg (0.22 mmol) DMF2.
A 5 ml solution was added. The reaction solution was stirred at room temperature for 9 hours, and then a phosphate buffer solution (pH 7) was added. The aqueous layer was extracted with ethyl acetate (three times), the extracted organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , and the solvent was removed under reduced pressure. Thin layer chromatography (developing solvent: hexane: ethyl acetate = 5: 1)
And 40 mg of 4-sec-butyl-3-fluoroisoquinoline was obtained. Yield 90%. ¹ H-NMR (500 MHz, CDCl ₃ ) δ 0.86 (3H, t, J = 7.3 H
z), 1.46 (3H, dd, J = 3, J _HF = 1.5 Hz), 1.82-2.01
(2H, m), 3.49 (1H, tq, J = 7.3, 7.3 Hz), 7.52 (1H,
dd, J = 7.9, 7.9 Hz), 7.70 (1H, dd, J = 7.9, 7.9 H
z), 7.98 (1H, d, J = 7.9 Hz), 8.14 (1H, d, J = 7.9
Hz), 8.81 (1H, s). ¹⁹ F-NMR (471 MHz, CDCl ₃ / C ₆ F ₆ ) 86.1 (1F, bs) ppm.

Example 5: Preparation of 2,4-dibutyl-3-fluoroquinoline 1,1-difluoro-2- (o-isocyanophenyl)
N-Butylmagnesium bromide (diethyl ether solution, 1.12) was added to a solution of 63 mg (0.29 mmol) of -1-hexene in 6 ml of toluene at room temperature under a nitrogen atmosphere.
M) 0.31 ml (0.34 mmol) was added. The reaction was stirred at room temperature for 15 minutes, then cooled to 0 ° C.,
1.2 ml of PA was added and stirred for 1 hour. The reaction solution is returned to room temperature and further stirred for 1 hour to obtain a phosphate buffer solution (pH
7) was added. The aqueous layer was extracted with ethyl acetate (three times), the extracted organic layers were combined, washed with brine,
After drying over Na 2 SO 4 and removing the solvent under reduced pressure, the residue was subjected to silica gel thin layer chromatography (developing solvent: hexane: ethyl acetate = 5: 1) to obtain 51 mg of 2,4-dibutyl-3-fluoroquinoline ( 0.20mmo
l) was obtained. Yield 69%. 1H NMR (500 MHz, CDCl3) δ 0.97 (3H, t, J = 7.6 H
z), 1.41-1.51 (4H, m), 1.63-1.71 (2H, m), 1.75-1.81
(2H, m), 3.01 (2H, td, J = 7.6, J HF = 2.4 Hz), 3.
06 (2H, td, J = 7.6, J HF = 1.7 Hz), 7.51 (1H, dd,
J = 7.9, 7.9 Hz), 7.61 (1H, ddd, J = 7.9, 7.9, 0.9
Hz), 7.91 (1H, dd, J = 7.9, 0.9 Hz), 8.04 (1H, dd,
J = 7.9, 0.6 Hz).

The above-mentioned general formula which is a raw material of the present invention is
Some production examples and spectral data of the β, β-difluorostyrene derivative represented by Chemical formula 6 will be described. Reference Example 1: Preparation of 2-o- (N-tosylaminomethyl) phenyl-1,1-difluoro-1-hexene 2-o- (Nt-butoxycarbonyl-N-tosylaminomethyl) phenyl-1 To a solution of 69 mg (0.15 mmol) of 1, -difluoro-1-hexene in dichloromethane (1.5 ml) was added trifluoroacetic acid 0.1 at room temperature.
7 ml (2.18 mmol) was added. The reaction solution was stirred at room temperature for 11 hours, and an aqueous sodium hydrogen carbonate solution was added. The aqueous layer was extracted with ethyl acetate (three times), the extracted organic layers were combined, washed with brine, dried over Na2SO4, the solvent was removed under reduced pressure, and the residue was subjected to silica gel thin layer chromatography- ( Developing solvent: Hexane: Ethyl acetate = 3:
1) to give 55 mg of 2-o- (N-tosylaminomethyl) phenyl-1,1-difluoro-1-hexene. Yield 100%. ¹ H NMR (500 MHz, CDCl3) δ 0.83 (3H, t, J = 7.0 H
z), 1.16-1.27 (4H, m), 2.14 (2H, br s), 2.44 (3H,
s), 4.05 (2H, d, J = 6.1Hz), 4.64 (1H, t, J = 6.1H
z), 7.07-7.12 (1H, m), 7.24-7.28 (2H, m), 7.31 (2
H, d, J = 8.1Hz), 7.337.36 (1H, m), 7.76

Reference Example 2: 1,1-difluoro-2-
Spectral data of (o-isocyanophenyl) -1-hexene 1H NMR (500 MHz, CDCl3) δ 0.87 (3H, t, J = 7.0H
z), 1.25-1.37 (4H, m), 2.38-2.43 (2H, m), 7.28 (1H,
dd, J = 7.7, 1.4 Hz), 7.35 (1H, ddd, J = 7.7, 7.7,
1.6 Hz), 7.38-7.44 (2H, m).

[0019]

According to the production method of the present invention, a fluorine-containing heterocyclic derivative can be produced in high yield.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Kokazu Wada             28-7 Kumagaya, Kokurakita-ku, Kitakyushu City, Fukuoka Prefecture             issue (72) Inventor Tatsuo Okauchi             1-8-27 Tenjin, Tobata-ku, Kitakyushu City, Fukuoka Prefecture             No. 301 (72) Inventor Minami Minami             9-8 Jiyugaoka, Munakata City, Fukuoka Prefecture F-term (reference) 4C031 DA01                 4C034 AL10

Claims (2)

[Claims] 1. A general formula: ## STR1 ## [In the formula, R ¹ represents a C1-C8 alkyl group, and X represents an isocyano group or an R ³ SO _n NHCH ₂ group. Where R ³
Represents a phenyl group which may be substituted with a C1 to C3 alkyl group, a C1 to C3 alkyl group or a C1 to C3
It represents a fluoroalkyl group, and n represents 1 or 2. ]
In β shown, and β- difluoro styrene derivatives, the general formula of 2 ## STR2 ## (R ^{2) -} [wherein, R ² represents a C1~C8 alkyl group. ] Or a nucleophilic species represented by the general formula: embedded image MH [wherein M represents an alkali metal]. ] The compound represented by the general formula: [Group wherein, -Y- is represented by -CR ² = N-, -N =
Group or represented by the _{^{CH- - (R 3 SO n)}} N-CH 2 -
And R ¹ , R ² , R ³ and n have the same meanings as described above. ] The manufacturing method of the fluorine-containing heterocyclic compound shown by these. 2. A general formula: Wherein, R ⁴ represents C2~C5 alkyl group, -Z- is a group represented by -CR ⁵ = N-, or a group represented by ^{-N = CH- - (R 3 SO} n) N-CH _It represents a group represented by _2- . Wherein R ⁵ represents an alkyl group C2-C5, R ³ and n are as defined above. ] Fluorine-containing heterocyclic compound represented by